Linggui Zhugan Decoction activates the SIRT1-AMPK-PGC1α signaling pathway to improve mitochondrial and oxidative damage in rats with chronic heart failure caused by myocardial infarction

Siyi Yu; Hang Qian; Dawei Tian; Mingming Yang; Dongfeng Li; Hao Xu; Jishun Chen; Jingning Yang; Xincai Hao; Zhixin Liu; Jixin Zhong; Handong Yang; Xinlong Chen; Xinwen Min; Jun Chen

doi:10.3389/fphar.2023.1074837

Linggui Zhugan Decoction activates the SIRT1-AMPK-PGC1α signaling pathway to improve mitochondrial and oxidative damage in rats with chronic heart failure caused by myocardial infarction

Front Pharmacol. 2023 Apr 5:14:1074837. doi: 10.3389/fphar.2023.1074837. eCollection 2023.

Authors

Siyi Yu^{1

2}, Hang Qian¹, Dawei Tian¹, Mingming Yang¹, Dongfeng Li¹, Hao Xu¹, Jishun Chen¹, Jingning Yang³, Xincai Hao⁴, Zhixin Liu⁵, Jixin Zhong⁶, Handong Yang¹, Xinlong Chen⁷, Xinwen Min¹, Jun Chen^{1

3

4

5}

Affiliations

¹ Sinopharm Dongfeng General Hospital (Hubei Clinical Research Center of Hypertension), Hubei University of Medicine, Shiyan, Hubei, China.
² Jiujiang No. 1 People's Hospital, Affiliated Jiujiang Hospital of Nanchang University, Jiujiang, Jiangxi, China.
³ Department of Immunology, School of Basic Medicine, Hubei University of Medicine, Shiyan, Hubei, China.
⁴ Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine), Shiyan, Hubei, China.
⁵ Institute of Virology, Hubei University of Medicine, Shiyan, Hubei, China.
⁶ Department of Rheumatology and Immunology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China.
⁷ Yunxi Hospital of Chinese Medicine, Shiyan, Hubei, China.

Abstract

Objective: To investigate the effects of Linggui Zhugan Decoction on mitochondrial and oxidative damage in rats with chronic heart failure after myocardial infarction and the related mechanisms. Methods: Chronic heart failure after myocardial infarction was established by coronary artery ligation. Heart failure rats were randomly divided into three groups: Model group (n = 11), Linggui Zhugan Decoction group (n = 12), and captopril group (n = 11). Rats whose coronary arteries were only threaded and not ligated were sham group (n = 11). Cardiac function, superoxide dismutase (SOD), malondialdehyde (MDA) contents, soluble growth-stimulating expression factor (ST2), and N-terminal B-type brain natriuretic peptide precursor (NTproBNP) levels were analyzed after treatment. Moreover, the level of mitochondrial membrane potential was detected by JC-1 staining, the ultrastructural of myocardial mitochondria were observed by transmission electron microscopy. The related signal pathway of silent information regulator factor 2-related enzyme 1 (SIRT1), adenylate activated protein kinase (AMPK), phosphorylated adenylate activated protein kinase (p-AMPK), and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is an important pathway to regulate mitochondrial energy metabolism, and to initiate mitochondrial biogenesis. The expression level was detected by Western blot and reverse transcription to explore the mechanism of the decoction. Results: Compared with the model rats, Linggui Zhugan Decoction significantly improved cardiac function (p < 0.05), reduced MDA production (p < 0.01), increased SOD activity (p < 0.05), reduced ST-2(p < 0.01), and NT-proBNP(p < 0.05) levels, increased mitochondrial membrane potential, and improved mitochondria function. In addition, Linggui Zhugan Decoction upregulated the expression of SIRT1, p-AMPK, PGC-1α protein, and mRNA in cardiac myocytes. Conclusion: Linggui Zhugan Decoction can improve the cardiac function of heart failure rats by enhancing myocardial antioxidant capacity and protecting the mitochondrial function, the mechanism is related to activating SIRT1/AMPK/PGC-1α signaling pathway.

Keywords: animal experiments; heart failure; mitochondria; myocardial infarction; traditional Chinese medicine.

Grants and funding

This work was supported by the National Natural Science Foundation of China (81400288, 81573244), Hubei Provincial Natural Science Foundation (2022CFB453), Foundation of Health Commission of Hubei (WJ2021M061, WJ2019F071), the Natural Science Foundation of the Bureau of Science and Technology of Shiyan City (Grant No. 21Y71, 19Y89), the Faculty Development Grants from Hubei University of Medicine (2018QDJZR04), and Hubei Key Laboratory of Wudang Local Chinese Medicine Research (Hubei University of Medicine) (Grant No. WDCM2022007), and the Advantages discipline Group (Medicine) Project in Higher Education of Hubei Province (2021–2025) (Grant No. 2022XKQT4).